Persistent infection of adult mink with the Aleutian mink disease parvovirus (ADV)leads to disturbances of immune regulation, including hypergammaglobulinemia, plasmacytosis, immune complex disease, interstitial and glomerulonephritis. Infection at the cellular level is noncytopathic and restricted. In contrast, infections in cell culture and in newborn mink are cytopathic and fully permissive. Studies in cell culture indicate that ADV induces programmed cell death (apoptosis) and is in fact dependent upon apoptosis for complete viral replication. We determined that the main ADV nonstrucutral protein (NS1) is cleaved twice by caspases and that mutagenesis of the caspase recognition sites interfers with virus replication. Furthermore, caspase cleavage is required for nuclear localization of NS1 and may be needed for NS1 to carry out fucntions in DNA replication and gene expression. This is the first demonstration that direct interactions between apoptotic effectors and viral proteins can facilitate replication of DNA viruses. Suppression of such interactions may enable persistence of ADV. Populations of native feral mustelids in Europe are declining. The presence of ADV infection has been documented in animals from Spain, France and Russia. More than 1 sequence variant of ADV appears to be circulating and these variants differ from previously identified isolates of ADV. ADV infections in wild mustelids may be contributing to their decline.